First-half goals from Charlie MacDonald and Shaun Williams - either side of Kevin Lisbie's equaliser - plus late strikes from Jabo Ibehre and Daniel Powell ensured a convincing victory for the Dons.
MacDonald gave them a dream start when he turned in Mathias Doumbe's low cross at the near post after only three minutes.
Lisbie equalised for Orient after 13 minutes, bundling in Jamal Campbell-Ryce's corner from a yard as the Dons appealed in vain for a foul on keeper David Martin.
But Williams restored the Dons' lead 10 minutes later when he stole in unmarked to head home Jay O'Shea's pin-point cross.
Substitute Ibehre made it 3-1 when he tapped in MacDonald's parried shot from close range before Powell netted a superb solo goal to seal the rout six minutes from the end.
MK Dons last week